Methylphenidate solution and associated methods of administration and produciton

ABSTRACT

A methylphenidate solution and associated methods of administration and production, which includes methylphenidate and at least one organic acid dissolved in a solvent system, where the solvent system includes at least one non-aqueous solvent. The solvent system may include water. The non-aqueous solvent can include, but is not limited to polyols and glycols and associated mixtures thereof. Pharmaceutical additives such as flavorings, colorants, buffers, preservatives and mixtures thereof may be optionally added to the methylphenidate solution.

FIELD OF THE INVENTION

The present invention relates to a methylphenidate solution, and more particularly to a pharmaceutically acceptable methylphenidate solution that exhibits sufficient chemical stability to provide a satisfactory shelf life.

BACKGROUND OF THE INVENTION

Methylphenidate HCl, CAS No. 298-59-9, is prescribed primarily to treat attention-deficit/hyperactivity disorder in children. Methylphenidate HCl is currently available as a solid based capsule or tablet, typically in 5 mg or higher dosages. Solid based formulations have inherent limitations, as capsules and tablets can be difficult to subdivide. It is therefore difficult to precisely administer any dosage other than multiples of the standard available dosages. Further, capsules and tablets present swallowing difficulties for some patients. A liquid formulation of methylphenidate HCl is therefore desirable.

Unfortunately, methylphenidate HCl has not been chemically stable in conventional liquid vehicles. The primary route of methylphenidate HCl degradation in solution is hydrolysis resulting in the formation of threo-α-phenyl-2-piperidineacetic acid (major) and 2-piperidineacetic acid, α-phenyl-methyl ester (minor) compounds. In addition to stability, the methylphenidate HCl solution must be pharmaceutically acceptable and have an acceptable taste.

It is therefore desirable to provide a methylphenidate HCl solution that is chemically stable, pharmaceutically acceptable and palatable.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, a methylphenidate solution is disclosed. This solution comprises, in the preferred embodiment, a therapeutic amount of methylphenidate HCl. The methylphenidate concentration is typically determined by the desired dosage volume. The preferred solution further comprises from about 0.5 mg/ml to about 5.0 mg/ml of at least one organic acid that enhances taste by providing tartness. The methylphenidate and the organic acid are dissolved in a solvent system that comprises at least one non-aqueous solvent. This methylphenidate solution is chemically stable.

In another aspect of this invention, a method for administering methylphenidate as an oral solution is disclosed. This method includes, in a preferred embodiment, preparing a solution containing a therapeutic amount of methylphenidate HCl and administering the methylphenidate HCl solution.

These are merely two illustrative aspects of the present invention and should not be deemed an all-inclusive listing of the innumerable aspects associated with the present invention. These and other aspects will become apparent to those skilled in the art in light of the following disclosure.

DETAILED DESCRIPTION OF THE INVENTION

Methylphenidate HCl is the preferred main component that is utilized with the present invention. While the hydrochloride form of methylphenidate is most commonly utilized currently, it is understood that the present invention would be applicable to any therapeutic form of methylphenidate compound, including but not limited to methylphenidate base and pharmaceutically acceptable salts of methylphenidate.

The concentration of methylphenidate HCl is variable and may be determined by the desired dosage and volume. For example, a 1 mg/mL methylphenidate HCl solution will yield a 5 mg dose per teaspoon oral dose, and a 2 mg/ml methylphenidate HCl solution will yield a 10 mg dose per teaspoon oral dose. These concentrations correspond to two dosages currently available, but can go higher. However, since the methylphenidate HCl is delivered in a solution, the dosage can be easily manipulated to prescribe a non-standard dosage. The concentration of methylphenidate HCl in the solution is preferably about 0.1 mg/ml to about 10.0 mg/ml.

A completely aqueous solvent system is not suitable for a methylphenidate HCl solution due to problems with solubility and stability. It is therefore necessary to provide a pharmaceutically acceptable solvent system in which the methylphenidate HCl is sufficiently stable to provide a suitable shelf life. In a preferred embodiment, the solvent system is at least about 50% non-aqueous solvent. The percentages given herein relate to the solvent system are weight/weight percentages of the solvent system only unless otherwise specified.

Another consideration in the formulation of the solvent system is taste. The overall taste feature of the solution is especially important in the area of pediatric medicine.

Glycol compounds have been found to greatly enhance the stability of methylphenidate HCl solutions. The glycol may be propylene glycol, polyethylene glycol or any other pharmaceutically acceptable polyalkylene glycol product such as those known in the art as the “PEG” series, or mixtures thereof. The PEG compounds are defined as chemical structures having 2 or 3 carbon atoms in the alkylene moiety of their chemical structures and a mean molecular weight of 200 to 4000.

A 100% glycol solution would provide a chemically stable methylphenidate HCl solution, however, the resulting solution would present other problems. At this level certain glycols would no longer be pharmaceutically acceptable. Propylene glycol, for example, would exceed acceptable safety levels. Furthermore, the taste would be less than desirable. While propylene glycol improves methylphenidate HCl stability, it imparts a bad taste at higher concentrations. Polyethylene glycol (hereinafter PEG) is therefor preferred for taste and safety purposes. In a preferred embodiment of the present invention the solvent system utilizes from about 10% to about 70% glycol, with about 10% to about 30% being more preferred, about 10% to about 20% being most preferred and about 15% being the optimal value.

Polyol compounds provide another pharmaceutically acceptable non-aqueous solvent. Acceptable polyol products include but are not limited to those having more than two hydroxyl groups in their chemical structures such as glycerin, sorbitol or simple sugars such as glucose and fructose and mixtures thereof. These polyols have an added feature in that they impart a sweet taste to the overall solution and act as a preservative. In a preferred embodiment, the polyol is glycerin. The solvent system of this invention includes, from about 30% to about 70% being preferred, about 40% to about 60% being more preferred, about 45% to about 55% being most preferred and about 50% being the optimal value.

While the solvent system may be completely non-aqueous, the addition of water improves the taste of the solution. In a preferred embodiment, the solvent system includes as much as about 50% water, with about 10% to about 45% being more preferred, about 30% to about 40% being most preferred and about 35% being the optimal value.

The organic acid included in the chemically stable methylphenidate HCl solution of the present invention preferably is any suitable pharmaceutically acceptable organic acid. Suitable organic acids include but are not limited to acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof. Organic acids, which enhance the taste of the solution, are especially useful. Citric acid, for example, adds tartness that is a taste enhancer, and may play a role in overall stability of the solution. The concentration of the organic acid in the solvent system is preferably in the range of about 0.5 mg/ml to about 5.0 mg/ml, with about 0.5 mg/ml to about 3.0 mg/ml being more preferred, about 0.5 mg/ml to about 1.5 mg/ml being most preferred and about 1.0 mg/ml being the optimal value.

Additional pharmaceutically acceptable additives may be added to the methylphenidate HCl solution, as is known in the art. These additives include but are not limited to flavorings, colorants, buffers and preservatives. The methylphenidate solution of the present invention may be stored in any non-reactive container. Glass and/or plastic containers are presently preferred.

The primary degradation product of the methylphenidate HCl solution is threoacetic acid, with a minor 2-piperidineacetic acid, α-phenyl-methyl ester component. Other minor reaction products have been noted, but are statistically insignificant.

The resulting methylphenidate HCl solution would typically be administered orally. However, the methylphenidate HCl solution could be administered intravenously or by inhalation if properly nebulized. Further, the methylphenidate HCl solution of the present invention may be adapted for use in a gel cap.

A therapeutically effective amount of methlphenidate HCl in a liquid solution may be administered to a patient having a disorder treatable by methylphenidate. Such disorders include, but are not limited to, behavioral disorders, Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, depression, specific dyslexias, brain dysfunction, cognitive decline in AIDS and AIDS related conditions, alertness in geriatric and Alzheimers patients. Further, a therapeutically effective amount of methlphenidate HCl in a liquid solution may be administered for use in recovery in stroke victims. The methylphenidate HCl solution may be stored in a non-reactive container for a predetermined period of time prior to administering the methylphenidate solution.

As is seen in the following examples, the methylphenidate HCl solution of the present invention is stable at 25° C. and also under accelerated storage conditions. Although the presently preferred solutions undergo some hydrolysis, the extrapolated hydrolysis rate predicts at least a two-year shelf life at 25° C.

EXAMPLE 1

A 1.0 mg/ml methylphenidate HCl was prepared. Glycerin, USP, 630.09 g and 350.03 g deionized water were placed into a beaker and stirred until a homogeneous solution was formed. Polyethylene glycol 1450, 181.45 g was added and stirred until dissolved. Citric acid, USP, 2.50 g was added and stirred until dissolved. Methylphenidate HCl, USP, 1.01 g added and stirred to dissolve. A grape flavoring was added and stirred to incorporate. The resulting formulation was transferred to HDPE containers in 30 ml quantities and the containers were sealed using an induction sealer. Samples were stored at 25° C./60% RH (T1) and 40° C./75% RH (T2). Samples were analyzed by HPLC for threoacetic acid (TA), 2-piperidineacetic acid, α-phenyl-methyl ester (E1), and methylphenidate at 2, 3, 6 and 9 month intervals. The samples were also tested for pH, color and odor. The data from Example 1 is outlined in the following Table 1: TABLE 1 Methylphenidate APHA Methyl- HCl 1.0 mg/ml Standard μg/ml μg/ml phenidate Months Temp pH Color Odor TA E1 % recovered 0 3.28 5 1 0.5 — 100.76 2 T1 3.18 5 1 1.91 2.11 100.50 2 T2 3.18 5 1 8.91 0.64 97.49 3 T1 3.10 5 2 2.6 0.3 99.93 3 T2 3.02 5 2 11.7 1.6 97.22 6 T1 3.01 5 2 4.9 0.1 99.92 6 T2 2.98 5-10 1 22.6 3.2 93.94 9 T1 2.97 5-10 2 6.8 0.2 97.71 9 T2 2.80 5-10 2 31.6 1.6 89.31 T1 = 25° C./ T2 = 40° C./ 1 = grape 2 = faint grape 3 = sour grape

EXAMPLE 2

A 2.0 mg/ml methylphenidate HCl was prepared. Glycerin, USP, 630.03 g and 349.99 g deionized water were placed into a beaker and stirred until a homogeneous solution was formed. Polyethylene glycol 1450, 181.50 g was added and stirred until dissolved. The citric acid, USP, 2.50 g was added and stirred until dissolved. Methylphenidate HCl, USP, 2.02 g added and stirred to dissolve. A grape flavoring was added and stirred to incorporate. The solutions were treated and analyzed as in Example 1.

The data from Example 2 is outlined in the following Table 2: TABLE 2 Methylphenidate APHA Methyl- HCl 1.0 mg/ml Standard μg/ml μg/ml phenidate Months Temp pH Color Odor TA E1 % recovered 0 3.21 5 1 0.6 — 100.28 2 T1 3.12 5 1 3.77 2.22 99.85 2 T2 3.12 5 1 18.70 1.11 97.61 3 T1 3.04 5 2 5.5 0.4 99.92 3 T2 3.00 5 2 24.4 3.0 97.45 6 T1 2.98 5 2 10.2 0.6 100.49 6 T2 3.00 5-10 2 47.7 6.0 94.81 9 T1 2.87 5-10 3 14.0 0.3 99.37 9 T2 2.76 5-10 3 67.6 3.0 91.63 T1 = 25° C./ T2 = 40° C./ 1 = grape 2 = faint grape 3 = sour grape

EXAMPLE 3

Three 2.0 mg/ml methylphenidate HCl solutions were prepared as in Example 2, resulting in the following compositions: Component Concentration (mg/ml) Methylphenidate HCl, USP  2.0 Glycerin, USP 630 PEG 1450, NF 181.5 Deionized water 350 Citric acid, USP  0.5, 2.5 and 5.0 Grape flavoring  0.5

The solutions were analyzed as in Examples 1 and 2 after storage at 25° C., 30° C., 40° C. and 50° C. at one and two month intervals. This data is outlined in the following Table 3: TABLE 3 Methylphenidate Citric APHA HCl 1.0 mg/ml acid Standard μg/ml μg/ml Methylphenidate Time Temp mg/ml pH Color Odor TA E1 % recovered 1 month T1 0.5 3.29 5 1 2.4 0.2 99.70 T1 2.5 2.90 5 1 2.8 0.0 97.24 T1 5.0 2.71 5 1 3.6 0.0 98.89 T2 0.5 3.32 5 1 3.0 0.4 99.75 T2 2.5 2.89 5 1 3.4 0.1 99.41 T2 5.0 2.72 5 1 4.2 0.0 99.58 T3 0.5 3.35 5 1 8.8 1.7 98.65 T3 2.5 2.91 5 1 8.7 0.8 98.36 T3 5.0 2.75 5 1 11.1 0.6 98.53 T4 0.5 3.31 5 1 23.7 6.2 98.31 T4 2.5 2.93 5 1 21.2 2.9 98.44 T4 5.0 2.78 5 1 26.6 2.4 97.35 2 months T1 0.5 3.29 5 2 5.0 0.6 98.29 T1 2.5 2.86 5 1 6.1 0.0 98.91 T1 5.0 2.70 5 2 8.1 0.0 98.83 T2 0.5 3.27 5 1 6.0 0.7 98.29 T2 2.5 2.83 5 1 7.1 0.3 100.29 T2 5.0 2.67 5 1 9.5 0.3 99.60 T3 0.5 3.30 5 2 24.4 5.1 96.74 T3 2.5 2.87 5 2 24.1 2.3 97.41 T3 5.0 2.71 5 2 30.4 1.9 97.57 T4 0.5 3.02 5 3 62.1 15.6 91.53 T4 2.5 2.85 5 3 59.1 9.3 91.72 T4 5.0 2.70 5 3 71.1 7.8 92.38 T1 = 25° C./60% RH T2 = 30° C. T3 = 40° C./75% RH T4 = 50° C. 1 = grape 2 = faint grape 3 = sour grape

Having described the invention in detail, those skilled in the art will appreciate that modifications may be made of the invention without departing from its spirit and scope. Therefore, it is not intended that the scope of the invention be limited to the specific embodiments described. Rather, it is intended that the appended claims and their equivalents determine the scope of the invention. 

1. A methylphenidate solution comprising: methylphenidate; and at least one pharmaceutically acceptable organic acid, wherein the methylphenidate and the at least one organic acid are dissolved in a solvent system and the solvent system comprising at least one non-aqueous solvent.
 2. The methylphenidate solution according to claim 1, wherein the at least one organic acid is present in the methylphenidate solution from about 0.5 mg/ml to about 5.0 mg/ml.
 3. The methylphenidate solution according to claim 1, wherein the solvent system further comprises water.
 4. The methylphenidate solution according to claim 3, wherein the water is up to 50% of the solvent system.
 5. The methylphenidate solution according to claim 1, wherein the at least one non-aqueous solvent is from about 50% to about 100% of the solvent system.
 6. The methylphenidate solution according to claim 1, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 7. The methylphenidate solution according to claim 1, wherein the at least one non-aqueous solvent is selected from the group consisting of polyols, glycols and mixtures thereof.
 8. The methylphenidate solution according to claim 1, further including at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof.
 9. A methylphenidate HCl solution comprising: about 0.1 mg/ml to about 10.0 mg/ml methylphenidate HCl; and about 0.5 mg/ml to about 5.0 mg/ml of at least one organic acid, the methylphenidate HCl and the at least one organic acid being dissolved in a solvent system, the solvent system comprising: up to about 50% water; about 30% to about 70% of at least one polyol solvent; and about 10% to about 70% of at least one glycol solvent.
 10. The methylphenidate HCl solution according to claim 9, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 11. The methylphenidate HCl solution according to claim 9, wherein the at least one polyol solvent is selected from the group consisting of glycerin, sorbitol, sucrose, fructose and mixtures thereof.
 12. The methylphenidate HCl solution according to claim 9, wherein the at least one glycol solvent is selected from the group consisting of propylene glycol, polyalkylene glycol products and mixtures thereof.
 13. The methylphenidate HCl solution according to claim 9, further including at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof.
 14. A methylphenidate HCl solution comprising: about 0.1 mg/ml to about 10.0 mg/ml methylphenidate HCl; and about 0.5 mg/ml to about 3.0 mg/ml of at least one organic acid, the methylphenidate HCl and the at least one organic acid being dissolved in a solvent system, the solvent system comprising: about 10% to about 45% water; about 40% to about 60% of at least one polyol solvent; and about 10% to about 30% of at least one glycol solvent.
 15. The methylphenidate HCl solution according to claim 14, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 16. The methylphenidate HCl solution according to claim 14, wherein the at least one polyol solvent is selected from the group consisting of glycerin, sorbitol, sucrose, fructose and mixtures thereof.
 17. The methylphenidate HCl solution according to claim 14, wherein the at least one glycol solvent is selected from the group consisting of propylene glycol, polyalkylene glycol products and mixtures thereof.
 18. The methylphenidate HCl solution according to claim 14, further including at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof.
 19. A methylphenidate HCl solution comprising: about 0.1 mg/ml to about 10.0 mg/ml methylphenidate HCl; and about 0.5 mg/ml to about 1.5 mg/ml of at least one organic acid, the methylphenidate HCl and the at least one organic acid being dissolved in a solvent system, the solvent system comprising: about 30% to about 40% water; about 45% to about 55% of at least one polyol solvent; and about 10% to about 20% of at least one glycol solvent.
 20. The methylphenidate HCl solution according to claim 19, wherein the at least one organic acid includes citric acid.
 21. The methylphenidate HCl solution according to claim 19, wherein the at least one polyol solvent includes glycerin.
 22. The methylphenidate HCl solution according to claim 19, wherein the at least one glycol solvent includes polyethylene glycol.
 23. The methylphenidate HCl solution according to claim 19, further including at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffer, preservatives and mixtures thereof.
 24. A method of treating a patient for a disorder treatable by methylphenidate which comprises administering a therapeutically effective amount of methlphenidate in a liquid solution.
 25. The method of treating a patient for a disorder treatable by methylphenidate of claim 24, the methylphenidate solution comprising: methylphenidate and at least one organic acid in a solvent system, wherein the solvent system includes at least one non-aqueous solvent.
 26. The method of treating a patient for a disorder treatable by methylphenidate according to claim 24, wherein the administering of the methylphenidate in a liquid solution is selected from the group consisting of oral administration, intravenous administration and inhalation administration.
 27. The method of treating a patient for a disorder treatable by methylphenidate according to claim 24, which further includes storing the methylphenidate solution in a non-reactive container for a predetermined period of time prior to administering the methylphenidate solution.
 28. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, wherein the at least one organic acid is present in the methylphenidate solution from about 0.5 mg/ml to about 5.0 mg/ml.
 29. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, wherein the solvent system further includes water.
 30. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, wherein the water is up to 50% of the solvent solution.
 31. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, wherein the at least one non-aqueous solvent is from about 50% to about 100% of solvent solution.
 32. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 33. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, wherein the at least one non-aqueous solvent is selected from the group consisting of polyols, glycols and mixtures thereof.
 34. The method of treating a patient for a disorder treatable by methylphenidate according to claim 25, which further includes dissolving at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof into the methylphenidate solution.
 35. A method of producing a chemically stable methylphenidate solution comprising: determining a dosage of methylphenidate; dissolving the methylphenidate and about 0.5 mg/ml to about 5.0 mg/ml of at least one organic acid in a solvent system, the solvent system comprising: up to about 50% water; about 30% to about 70% of at least one polyol solvent; and about 10% to about 70% of at least one glycol solvent.
 36. The method for producing a methylphenidate solution according to claim 35, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 37. The method for producing a methylphenidate solution according to claim 35, wherein the at least one polyol solvent is selected from the group consisting of glycerin, sorbitol, sucrose, fructose and mixtures thereof.
 38. The method for producing a methylphenidate solution according to claim 35, wherein the wherein the at least one glycol solvent is selected from the group consisting of propylene glycol, polyalkylene glycol products and mixtures thereof.
 39. The method for producing a methylphenidate solution according to claim 35, further including dissolving at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof into the methylphenidate solution.
 40. A method of producing a methylphenidate HCL solution comprising: determining a dosage of methylphenidate HCL; dissolving the of methylphenidate HCL and about 0.5 mg/ml to about 5.0 mg/ml of at least one organic acid in a solvent system, the solvent system comprising: about 10% to about 45% water; about 40% to about 60% of at least one polyol solvent; and about 10% to about 30% of at least one glycol solvent.
 41. The method for producing a methylphenidate HCl solution according to claim 40, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 42. The method for producing a methylphenidate HCl solution according to claim 40, wherein the at least one polyol solvent is selected from the group consisting of glycerin, sorbitol, sucrose, fructose and mixtures thereof.
 43. The method for producing a methylphenidate HCl solution according to claim 40, wherein the wherein the at least one glycol solvent is selected from the group consisting of propylene glycol, polyalkylene glycol products and mixtures thereof.
 44. The method for producing a methylphenidate HCl solution according to claim 40, further including dissolving at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof into the methylphenidate HCl solution.
 45. A method of producing a methylphenidate HCl solution comprising; determining a dosage of methylphenidate HCl from about 0.1 mg/ml to about 10 mg/ml; dissolving the of methylphenidate HCL and about 0.5 mg/ml to about 1.5 mg/ml of at least one organic acid in a solvent system, the solvent system comprising: about 30% to about 40% water; about 45% to about 55% of at least one polyol solvent; and about 10% to about 20% of at least one glycol solvent.
 46. The method for producing a methylphenidate HCl solution according to claim 45, wherein the at least one organic acid is selected from the group consisting of acetic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and mixtures thereof.
 47. The method for producing a methylphenidate HCl solution according to claim 45, wherein the at least one polyol solvent is selected from the group consisting of glycerin, sorbitol, sucrose, fructose and mixtures thereof.
 48. The method for producing a methylphenidate HCl solution according to claim 45, wherein the wherein the at least one glycol solvent is selected from the group consisting of propylene glycol, polyalkylene glycol products and mixtures thereof.
 49. The method for producing a methylphenidate HCl solution according to claim 45, further including dissolving at least one pharmaceutical additive selected from the group consisting of flavorings, colorants, buffers, preservatives and mixtures thereof into the methylphenidate solution. 